Immunotherapy notes Part 2 PDF

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Extensive immunotherapy notes on lectures with primary source literature part 2...

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Management of toxicities from immunotherapy (2017) ● Toxicities from checkpoint inhibitors are infusion reactions and immune-related adverse events or adverse events of special interest ○ Most frequent irAEs are skin, colon, endocrine, liver, and lungs ● irAE from anti-CTLA4 at 3 mg/kg occur in 60%-85% of patients ○ Mostly grades 1 and 2 (less serious) ○ 10%-27% are grade 3 to 4 ○ 2.1% AE related deaths found in first phase 3 trials ○ Toxicity starts within 8-12 weeks of treatment, usually in the skin ■ Appear to be dose dependent, .3 mg/kg produced no grade 3 AEs ■ Increasing dosage increased irAE rate ● PD-1 blockade frequently causes fatigue (16-37% for anti-PD1, 12-24% for anti-PDL1) ○ High grade toxicities are less common, although some AE was documented in 74-85% of patients for melanoma (only 12-20% are grade 3-4) ■ NSCLC sees 58% and 7% respectively ■ Carcinoma has 79% and 19% ■ This describes nivolumab ○ Similar lower numbers occur for pembrolizumab

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Combination immunotherapy has only been approved in melanoma, and 95% of patients experience adverse events, 55% experienced grade 3+ Most irAEs occur early, from weeks to 3 months (could be as long as a year after treatment ends) ○ Use of tissue biopsy for diagnosis is not established

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Some suggest it for higher grades (3 and 4) if there is doubt about the exact cause of the ailment and the outcome affects management Patient selection should be partially based on ability to handle and develop and irAE ○ Analyze patient and family history, physical condition, autoimmune diseases, baseline laboratory tests, and radiological exams ○ Autoimmune disease puts you at high risk for worsening the disease ○ irAEs for one kind of therapy increases risk for others ○ Once AEs begin, immunotherapy should often be discontinued ■ Should be put on immunosuppressive drugs ■ Can’t use immunosuppression for too long or opportunistic infections will likely begin to pop up (>6 weeks) ■ Immunosuppression doesn’t appear to affect ICP outcomes in cancer Skin AEs are comparatively frequent for patients with MoAbs ○ Typically develop in the first couple weeks of treatment ○ Serious AEs are rare, usually don’t require treatment discontinuation ○ Vitiligo associated with good clinical response for melanoma ○ Rash, pruritus, and vitiligo are most common ○ Likely that incidence is underreported, since clinical trials don’t involve routine full body exams by dermatologists ○ 4 broad groups: inflammatory reactions, skin lesions, keratinocyte alteration, melanocyte alteration Diagnosis and biology for skin AE ○ First need to rule out any other sources, like infection or existing skin conditions ○ Severity evaluated using examination of the mucosal areas, analysis of general patient status, and potentially a blood cell count with liver/kidney tests ○ Eliminates possibility of dermatological emergency involving life threatening syndromes like DRESS or toxic epidermal necrolysis ○ In these cases, immunotherapy is discontinued and hospitalization is necessary ○ Use “Common Terminology Criteria for Adverse Events” ■ It includes quantitative descriptions of disease manifestation and the emergence of other symptoms to describe the reaction grade

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Thyroid gland disorders ○ Incidence has increased with introduction of checkpoint inhibitors ■ Not very clear why, thought to be mediated by T cells ○ Hypothyroidism is more common than hyperthyroidism ○ Cohort of NSCLC treated with pembrolizumab were then given thyroid stimulators and measured for anti-thyroid antibodies ■ About 11/51 needed thyroid hormone replacement, and about 9 of those 11 were positive for anti-thyroid antibodies ■ Only 8% of patients who didn’t develop thyroid dysfunction needed hormone replacement ■ Could indicate that autoimmune thyroid disease and thyroid dysfunction as an adverse event might have similar pathogeneses ○ PD-1 or PD-1/CTLA4 are most common causes of thyroid dysfunction ■ CTLA4 saw 1-5% incidence at 3 mg/kg, and up to 10% at 10 mg/kg ■ anti-PD1 saw 5-10% incidence, and combination caused 20% ● Events are rarely higher than grade 2 ● Routine blood tests should be conducted at least monthly ○ Management of thyroid disorders:

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Hypothyroidism: use of thyroid hormone in cases of fatigue, more extreme cases may also need beta-blockers or (rarely) steroids Hormone replacement is typically long lasting

■ Hypophysitis ○ Involves inflammation of anterior lobe of the pituitary gland, and it has extremely rare until anti-CTLA4 became used ○ Have been reported 1% at 3 mg/kg, 16% at 10 mg/kg, and 8% for combination ○ Specific causes are unclear ○ Headaches and visual disturbance should be taken seriously ■ Could also result from cerebra metastasis or other cerebral disease ■ Should use brain MRI or blood tests of hormone levels to diagnose ○ Management typically involves interruption of immunotherapy ■ Hormone replacement treatment should be instigated immediately ■ High-dose steroids necessary for neurological problems, don’t counteract hormone deficiency ■ Typically immunotherapy use can be restarted Type 1 Diabetes mellitus ○ More common in PD-1 blockade than CTLA4 ○ Blockade of PD-1 triggers development of diabetes via CD8 T cells ○ Patients should have blood glucose levels monitored, as type 1 or 2 diabetes could potentially emerge ○ Steroids should likely be avoided ○ Typically, immunotherapy should be interrupted until insulin substitution effectively regulates the patient Immune-related Hepatotoxicity ○ Hepatitis (mostly grade 1 and 2) occurs in 5-10% of patients on single dose therapy and in 25-30% of those treated with combination (15% of this is grade 3) ○ Assessment for hepatitis is needed before each treatment cycle ○ Therapy initiation should not be delayed while awaiting serological results unless there are other apparent causes ■ Live biopsy should be considered to assist diagnosis ○ Management of grade 2 or higher involves immunotherapy interruption ■ After ruling out other causes, persistent grade 2 infection merits steroids ■ Checkpoint therapy can resume after tapering the steroid in the case of improvement ■ For grade 3 or 4, checkpoint inhibitor is permanently withheld ● Steroids started immediately ● Sometimes immunosuppressors can be helpful ■ Hepatitis should be resolved within 4-6 weeks ● If not, re-diagnosis is likely necessary GI Toxicity ○ Diarrhea in 27-54% of anti-CTLA4 patients ○ Typically a third of patients have diarrhea and 8-22% have colitis ○ One of the most severe AEs associated with anti-CTLA4

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■ Usually first AE to cause therapy interruption ■ Could even cause colon perforation or enterocolitis ○ Non-steroidal anti-inflammatories increased risk of enterocolitis ■ Can occur after 1-10 treatment cycles ■ Most common symptom is diarrhea ■ Also experience abdominal pain, weight loss, fever, vomiting ■ Anemia, increased fecal levels of calprotectin ○ Non severe diarrhea can be treated with anti-diarrheals and electrolytes ■ More severe requires therapy interruption and steroid use ■ May also require infliximab ■ Vedolizumab (MoAb for gut-specific immunosuppressors) appears to be extremely effective, but safety isn’t confirmed as of writing ■ Restarting of immunotherapy seems to be highly correlated with enterocolitis remission ○ No apparent biomarkers for predicting colitis ■ Some gut microbiota appear to be associated ○ Doesn’t seem to be a significant problem for anti-PD1 ○ Combination therapies result in higher rates of GI toxicity than ipilimumab by itself Immune related pneumonitis ○ More common in anti-PD1 by about 1.5 to 2 times, has been observed in both ■ Combination therapy increases likelihood up to 3 times ○ Can be fatal, rarely progresses even in spite of immunosuppressives ○ Low grade coughs and shortness of breath are common ○ Grade 3 or higher only occurs in 1-2% (dyspnea), 2-9% (cough) ○ Pneumonitis is rare, 2-4% of patients (1-2% are 3+) ○ Tends to occur later than AEs ○ Typically, lung biopsy and bronchoscopy aren’t needed ■ Can assist in diagnosis of opportunistic infections/strains though ○ Management needs immunosuppressives ■ Use bronchoscopy to rule out infections ● If you can’t rule out infection, use broad antibiotics ■ Grade 3-4 requires permanent discontinuation of immunotherapies, hospitalization, and steroid use ■ Steroids should be tapered carefully, as resurgence during tapering is common Rare toxicities ○ Neurological: ■ Reported as 1%, but may actually be higher (3-6% in monotherapies and up to 12% in combinations) ■ Necessary to rule out the underlying cancer and other possible causes ■ All but grade 1 should be treated with withheld immunotherapy and high dose steroid therapy ○ Cardiac:

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■ Less than 1% ■ Over 4 times higher in combination than monotherapy ■ Immunosuppressives are necessary if steroids don’t work Rheumatological: ■ Occur in 2-12%, more common with PD1 ■ Analgesia or NSAIDs (pain relief) works for mild symptoms ■ Severe requires rheumatologist consultation and steroids or TNF blocking agents Renal: ■ Less than 1% for monotherapy, as high as 4.9% in combination ■ Serum sodium, urea, etc should be measured before every infusion ● Also stop nephrotoxic drugs, rule out infections, UT issues ■ Withhold inhibitory therapy in event of renal dysfunction ■ Renal biopsy can be used for difficult diagnoses ● Often found interstitial nephritis with lymphocytic infiltration Ocular: ■ Less than 1% of patients ■ Either ocular inflammation, orbital inflammation, or retinal disease ■ Treatment depends on severity, may include topical or systemic steroids ■ anti-VEGF can be used for choroidal vascularization Haematological: ■ Rarely been described, but do seem to occur ■ Includes lethal anemia, autoimmune hemolytic anemia, or immune purpura ■ Optimal treatment is hard to say besides use of steroids and immunosuppressants while consulting with a specialist Allograft rejection: ■ Not apparently caused by ipilimumab ■ Can be caused by PD-1 ■ Must be considered in therapy options

Current challenges in cancer treatment (2016) ● EGFR was found to be a biomarker, NSCLC patients can benefit from EGFR tyrosine kinase inhibitors (not an immunotherapy) ● Showed the effectiveness of using a genomic testing to find druggable targets ● Matched therapies achieved longer survival rates ● Only works best when the tumor is experiencing oncogene addiction, so tumors with multiple driver mutations might not react well ● Best conducted using throughput next-gen sequencing like customized gene panels and whole exome/genome panels ○ Gene panels can detect multiple mutations (up to ~200) at once ○ NGS panels are PCR or hybrid capture based

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PCR subject to false positives (polymerase induced artifacts)/ false negatives (lack of DNA) ■ Typically used for point mutations, so they need to be combined with other techniques to cover other genomic abnormalities ■ Hybrid capture panels are more reliable, but require superior infrastructure ○ Whole exome is typically used for research purposes since they require massive genomic datasets, which aren’t suitable for therapeutic purposes ■ Also there’s lots of extraneous data which isn’t useful ■ It’s also expensive Clinical trials should be driven by biomarkers ○ Precision medicine should be tested based upon similarities in mutations ○ Different tumors can have similar mutations ■ Mentions a phase 2 paper for “nonmelanoma BRAF V600 mutants” ■ These are called basket trials ○ Umbrella trials involve only one tumor type, with different mutations ■ These mutations can be grouped to create a control arm ○ Randomly assigning genotype selected patients to tailored vs conventional therapies instead of specific drugs can work ○ N of 1 trials compares the outcome of personalized therapy against the most recent nontargeted regimen on an individual basis ○ This needs to be modified to account for tumor heterogeneity Heterogeneity typically includes majority of mutations in all tumors ○ Typically the same drivers are recurrent and dominant ○ Ideally makes a single site biopsy still feasible ○ Doesn’t account for some subclonal populations supporting growth of nearby dominant cells, which would still create a range of aggression within a single tumor and allow for subclonal populations to help resist drugs ○ Three mechanisms of genomic resistance: ■ Those that imply second genomic alterations in the drug target ● Use of third-generation drugs can be effective ■ Those that reactivate a genomic pathway ■ Those which allow for bypass of typical signaling pathways ● Combination strategies targeting common bypass tracks are promising ○ Bottom line is repeated biopsies are needed to monitor tumor mutation ■ Liquid biopsies might make this easier Paper discusses a lot of basics of immunotherapy outlined in previous summaries Discusses how second-line nivolumab shows a 3 month improvement in OS vs chemo Found PD1 to have a better toxicity profile than chemotherapy ○ PD1 long term survival is limited to 10-20% of patients Echoes how discouraging cancer vaccines are Discusses the PD-L1 positive biomarker breakthrough

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Raises the point that some tumors might be constitutively expressing PD-L1, which would prove to be a less effective biomarker than in tumors which are upregulating PD-L1 due to interferon ○ Some PD-L1 negative patients also benefit from treatment ■ Indicates that there may be too many unanswered questions for an ideal biomarker as of now ■ More definition of target cells, PD-L1 localization, and overexpression contexture is likely needed Suggests using genomic contexture of the tumor as an immunotherapy biomarker ○ Tumor profiling and manipulation of neoantigens may determine therapy response ○ Speaks of promise of adoptive T cell therapies in this regard General conclusion is the need for combination therapies - “There is no magic bullet” ○ Speaks of personalized combinations around PD1 as being the cornerstone of next generation oncology ○ Toxicity will be the limiting factor

https://www.ncbi.nlm.nih.gov/pubmed/31561846 Monoclonal Antibodies serve as promising cancer therapeutics ○ PD-1 (programmed death-1) as an immune checkpoint inhibitor (ICI). Natural Role of PD-1

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Checkpoint to diminish T-cell activation, mostly in later phases of activation to prevent T-cell auto-reactivity. ○ PD-1 receptors w/ the PDL-1 weaken T cell activation and inhibit active T-cells. Examples of known PD-1 inhibitors. ○ Pembrolizumab and nivolumab Examples of known PDL-1 Inhibitors ○ Atezolizumab and darvulumab MOA of Inhibitors ○ Bind T-cell surface or tumor surface and block tumor cell receptors from turning off activated T cells thereby allowing anti-tumor activity to continue. Lung Cancer ○ Different Categories identified by histology ■ Non small cell lung cancer (80-85%) ■ Small cell lung cancer (15-20%) ■ Lung carcinoid tumors (6 had a PFS time of 2.85 vs 2.19 months

41 patients that went longer than 2 months PFS were included in the above charts. In chart A, the responders were compared to the nonresponders. VUS >3 23.2 months vs 2.3 months. ctDNA >6 PFS 23.3 versus 2.3 months. Overall survival was 15.3 months. OS was not reached in >3 VUS patients but was 10.72 in 6 ctDNA patients but was 10.79 in...